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Registration for our 2105 MLD Family Conference in Newark Delaware is underway and closes in just a couple of weeks. If you are a MLD Family we’re anxious to have you register.

Many of your MLD Family will be there to meet, share, and socialize with.

Please bring your MLD loved one with you – we not only want to meet them, we have a special professional photographer to take your family’s photo while capturing the spirit of our special loved ones and the MLD journey through photography.

You will again find familiar faces in the Respite room to care for your other children and your MLD loved ones.

Those with MLD angels are always lovingly encouraged to attend – you have so much to share with the rest of us and you will surely find folks that “just get it”.

* Shire will be discussing their ERT clinical trial status and sharing some interim results.

* Newborn screening … updates on the assay development, federal/state policy & actions, and the RUSP Roundtable we are organizing … and how you can help!

* On Saturday, as usual, you will drive the Practical Care agenda, … including a discussion about medical marijuana & CBD oil .

* We’re working hard on a special fun Saturday evening event, a memorial butterfly release, the traditional MLD “bashing”, and MLD After Hours.

We have many of the global MLD experts attending so you can meet them and ask any questions you may have.

With travel support and scholarships available, all you need to do is register! You can defer paying the modest registration fees for a few weeks if you need to, but we want to know you are coming so we save the right number of sleeping rooms!

Earlier last month we had the opportunity to see several presentations about the Leukodystrophy Center of Excellence (CoE) at Children’s Hospital of Philadelphia(CHOP), which opened today, May 1st.

The mission of the [CHOP Leukodystrophy CoE] center is “to deliver cutting-edge, integrated, multidisciplinary clinical care, diagnostic evaluation, and therapeutics to infants, children and youth with inherited white matter disease.”

We are excited about the multi-disciplinary approach of collaborative and comprehensive care this center is now providing for leukodystrophy patients and families. Under the directorship of Dr. Amy Waldman, care plans are being developed by teams of specialists, with a designated CHOP care coordinator and extensive family/caregiver involvement. The CHOP team will include a standard suite of specialists and will include additional experts from other CHOP specialties who will come and go as situations arise. Appointments and treatments will be consolidated into one day’s visit, where possible, so families don’t have to make multiple trips to the CoE thereby improving the scope of care and reducing the burden on families and patients. We are planning to have representatives from CHOP come and present at our MLD Family Conference™ in Delaware this July. We also hope to hear 1st hand reports from Philly area families about the CHOP CoE .

MLD Foundation is an avid supporter of helping these existing centers work more closely together to improve patient care for all the leukodystrophies and to improve how network and clinical data is gathered, shared, and studied to improve care, advance understanding, and expedite therapies. This will require helping the centers to work more closely, establishing common methodologies, expanding their capabilities to serve all leukodystrophies, and putting more uniformity and structure into the clinical care and research strategies. As resources become available the program can be expanded to include CoE’s in other parts of the country so every leukodystrophy family has a CoE close to them.

We are actively working with GLIA (Global Leukodystrophy Initiative – a two-year old international collaboration of leukodystrophy clinical and research experts), industry pharma partners, advocacy groups, and other MLD experts to develop standards of care, registries for common data collection, resource directories, access to experts, training and awareness, and maybe even provide some seed funding to help new centers to launch. Imagine if these experts were able to implement CoE’s for leukodystrophies at all of their home medical centers – what a powerful and accessible clinical care and research force that network would be.

MLD Foundation’s OpenNHS Manifesto offers a peek into how we think pre-clinical Natural History Study collaborations should operate. We’re thinking the CoE picture should have similar overriding and undergirding principles. Maybe an OpenCoE Manifesto is in order?

Today, February 28th, is Rare Disease Day (actually RDD is the 29th – but we don’t have one of those this year!).

Today we celebrate and recognize the 1 in 10 of us that have one of the 7,000+ rare diseases … over 30 million here in the US and 350M worldwide, what would be the world’s 3rd largest country (more populated than the US) if we all lived in one place. Less than 5% of the diseases have a formal therapy, over 50% of the diseases affect children, and 30% of those children will not live past the age of 5. In a world where doctors hear hooves and see horses, we are all zebras. A good infographic about Rare disease can be found here.

Recognizing this, MLD Foundation, both Teryn and I, spent the week in Washington DC for Rare Disease Week. I wanted to share some reflections and highlights of our week with you.

On the lighter side, we joined with others at the Carnegie Institute of Science for a reception and a screening of the film RARE. It was a time to catch up with many friends we have come to know through our work over the years … and to meet many more new advocates. There was a preview screening of a film called Banner on the Moon.

The social highlight of the week was not watching films, it was the RAREARTIST reception
Thursday evening. I was able to talk to three of the artists. 13-year-old Cody Spader’s Therapy Dog shares his journey through surgery for complex seizures. 9-year-old Tegan Skye was dressed in a cute light blue dress and when I approached her to ask about her picture as the event started she was uncertain what to say … but once she became comfortable I learned that her father has Chordoma and needed to travel several thousand miles for specialized surgery. Their family dog had always comforted dad at home by laying in his lap, but the dog could not travel to the hospital. Little Tegan was very concerned that her dad be comforted so she drew this picture for her dad to put up in his hospital room while he recovered. Hearing her tell this story not only brought a tear to my eye, but it also reminded me that no family member is every un-affected by rare disease.

On the business side of things, I was asked back for the second year to be the Moderator and Host for some 250 advocates from all 50 states at RDLA’s all-day Legislative Conference. My job, besides keeping the event logistics running and on time (after 8 hours of sessions we ended just 90 seconds late), was my responsibility to welcome, include, educate, and engage the advocates so they had everything they needed to be powerful advocates during their Capitol Hill meetings the next day. My brief motivational kick off talk, What Do You See, was based on the idea that what others see in us is not the inadequacies we see when we look into the mirror. The advocates in that room needed to know they were leaders and perfectly capable of representing their specific disease communities, and when we divided 30 million Americans across each of them they were actually representing about a quarter of a million each! We spent the day learning from and interacting from panelists which include legislative aides and a chief of staff from the Hill, advocacy leaders, lobbying firms, and many more.

In amongst some 1200 researchers at the LDN/WORLD meeting on Lysosomal Storage Diseases a couple of weeks earlier we met a Pennsylvania mother with a child with a rare disease. She was passionate about learning about the research and supporting families with her daughter’s form of MPS. After several conversations over the course of a couple of days at that meeting, we invited her to DC to share some of her passion with her federal representatives. Registration was closed but we got her a place and onto the Hill day schedules. She wrote me a quick note of appreciation yesterday – I was so thrilled she was engaged, connected and now not alone! She joined the over 50% of the advocates at the conference who were 1st timers on the Hill.

On Wednesday we all put on our red RDLA scarfs and headed to meetings with our Congressmen and Congresswomen. In between meetings we generally had to do a lot of walking to get between offices and across the Capitol from the House office buildings to the Senate office buildings. We saw dozens of other red-scarved Rare Disease advocates heading opposite directions. The feedback from Advocates was about positive engagements as they discussed the 21st Century Cures Initiative, CURE (Compassionate Use), OPEN Act (Orphan Products), and Dormant Products /MODDERN (repurposing drugs). I can’t count the number of times we were stopped as advocates, 1st timers and returning “old” friends mentioned how empowered and productive they were being … all for all of you!

We finished the week with an all day meeting on Friday at the NIH. We heard from Francis Collins, Director of the NIH and a huge fan of Rare Diseases, the FDA, NCATS, and a very interesting panel of creative patient-advocates turned science-advocates including Jill Wood of Jonah’s Just Begun/Phoenix Nest, Matt Might of NGLY1.org, and Barbara Handelin of BioPontis Alliance. Discussions included basic science, policy, funding, biotech start-ups, novel collaborations, clinical trials, newborn screening, identifying undiagnosed and mis-diagnosed rare disease patients, and much more.

We are humbled to be able to represent you as participants and leaders in Washington DC, and around the world. Personally, our passion is always driven by MLD, but we know that a rising Rare Disease ocean benefits all diseases, including MLD.

You are special, you are RARE, but RARE is not rare, and you are not alone!

recognizes the importance of NHS to better understand the disease and as a baseline to determine efficacy and obtain regulatory approval of new therapies.

calls for the NHS study team to be well-informed about MLD and to give back to the participants ideas and insight into improving the participants quality of life and ongoing clinical care.

calls for study sponsors to collaborate pre-clinically up front with other researchers and industry to design a study that meets the sponsor’s needs as well as reasonably anticipated future needs

calls for study data to be open and accessible as raw data (in its entirety) to future researchers. The Manifesto recognizes that some limited time protection may be necessary to honor publishing and IP rights.

At the DC meeting there was extensive discussion and sharing of perspectives and concerns about openNHS from many points of view.

We are pleased to report the meeting was a success on all fronts! MLD Foundation, on behalf of those affected with MLD and the ongoing research community, was able to facilitate full support of the Manifesto and will be working with MLD collaborators in general, as well as Shire as sponsor of the current US late infantile NHS, to implement the Manifesto on current and future MLD Natural History Studies.

We look forward to sharing more specifics about what this means to MLD families and NHS study participants in the near future.

We will also be sharing our success with other advocacy groups with the hope that they too can call for openNHS in their communities.

The Enzyme Replacement Therapy HGT-1110 Phase I/II clinical trial has been fully recruited. Patients are participating from three continents; Europe, South America, and Australia.

The primary purpose of a Phase I/II clinical trial is to study safety and to establish a target dosage for further study.

The trial lasts 40-weeks so the last patient should complete their primary end point in March 2015 or thereabouts. Allowing 3-4 months for data analysis and review, there might be some results reported Summer 2015.

Great Patient Focused Drug Development (PFDD) meeting at the FDA Tuesday discussing patients perspective on the neurological inborn errors of metabolism (IEM). Dean Suhr, president of the MLD Foundation, spoke on the second panel of the day and was able to both share and stir the pot a bit with regard to some of the patient perspectives on what we want in therapies, risk/benefit, access to trials in the US, compassionate/named access, patient reported outcomes, and consent. It’s not all about statistics and biochemistry – we have life to live!

View from the panel of ½ of the audience of advocates, families, researchers, and industry at the FDA PFDD meeting on IEM.

Also met the Medical Officer at the FDA assigned to gene therapy and made sure she talked to Becky Vivian, a MLD mom who was there with her kids Eli and Ella showing the remarkable results from the Italian gene therapy clinical trial.

The Vivian family – both kids had the Italian Gene Therapy and are on no post-transplant drugs. They, and the rest of the trial participants, are doing great.

In the next couple of days we’ll be sharing how to add your voice to the formal written docket for this meeting. This is our opportunity for the MLD community to be heard so we hope for many of you to share.

A MLD grandmother was also present – we had a great talk. Turns out she is a researcher and has done some work at the NIH. She wants to work with us … and you … to write a paper on bone marrow transplant outcomes. We’ll have more to share on that soon too.

Added 6/18 … be sure to also visit http://PFDD.US for more information and to join the discussion there on this meeting.

On the 24th of this month we are convening a meeting of MLD researchers, industry, and academia in Washington DC to discuss openNHS, a project we hope starts with MLD but quickly expands to all rare diseases.

We’ve prepared and sent out an openNHS Manifesto to frame our discussions. Please read this document and let us know if you have any feedback, questions or suggestions.

Like this:

A new Natural History Study (NHS) for MLD was launched a few weeks ago. We have taken the bold step of recommending that families NOT participate in this study … for now:

It is our belief that all natural history studies be OPEN access, meaning the study data be maximized by being made available to other researchers from other academic institutions and companies, and be as collaborative as possible. Properly designed studies will protect your privacy while maximizing the use of your data to facilitate longevity in MLD research.

In our opinion this new NHS does not adequately meet this criteria. We are (February 2014) in discussions with the study sponsors to address these concerns.

This study is the fourth NHS that we are aware of for MLD and was launched by a long-standing pharmaceutical partner and MLD collaborator, Shire. We want to be clear that our don’t participate for now recommendation is not a Shire specific issue nor is Shire resisting discussing our concerns. Further, this “not participate” stance is not because there are any fundamental scientific problems with the study, rather it’s that we want to optimize the value, usefulness, and knowledge gained from this rare disease Natural History Study for the researchersand for the patients.

We are actively working to bring the MLD community of Shire, GSK, Biomarin, several academic institutions, several other advocacy groups, and even some local treating clinicians together in the next month or two to collaboratively work on the following concerns and requests so we can get back to helping recruit for this study.

We are asking for two things before we encourage families to participate in this, or any other Natural History Study …

OPEN collaborative Natural History Studies … meaning that the study is designed collaboratively and all ofthe the collected RAW data is made available openly to all future researchers.

MLD natural history studies are invasive and painful for the child who participates (nerve conduction and Lumbar Puncture/Spinal Taps). They also require a commitment that significant time and energy be put forth by families to make the repeat their visits to the study center knowing that they will not be receiving any therapy clinical trial access, i.e. they are giving to hopefully help the next generation of patients, not their own children.

Today, the current practice is one company designs their own NHS, collects and silos the raw data, uses the data for their application with the FDA, and then publishes the highlights. Since only the summary data is published, the next company has to start from scratch with their own new study, engaging & testing more patients, etc. That requires twice as many patients, twice as much patient sacrifice, twice as much cost, and perhaps twice as much time. We don’t have a large enough community or enough time to double and triple dip – in fact, yesterday we lost another MLD patient, the 9th we know of this year.

The results from natural history studies are necessary for a new FDA/EMA therapy approval applications,however, these patients are untreated so their data is independent of any particular therapy. Hence a NHS, just like developing a newborn screen, is a matter of common concern, not competitive advantage.

We are asking that Natural History Studies be collaboratively designed, collaboratively implemented, and all RAW data (not just the published summaries) be available for any researcher to access for any future study. This collaborative approach will likely involve cost sharing as well so it’s complicated to set up but this approach allows us to gather the data as efficiently and as quickly as possible – while optimizing the “use” of the patient community.

Give back to the patients/families with each NHS study visit … give the families information to take home after each visit to help them improve quality of life for their loved ones.

The NHS study centers have experts in gathering the NHS data, however, while they may understand lysosomal disease or leukodystrophies in general, they are generally not currently providing any direct MLD clinical feedback to the patients.

We already have a model for this in our community, the NDRD in Pittsburgh. In fact, families visit and re-visit the NDRD from literally across the country for the clinical expertise and are then recruited into the natural history studies. The NDRD has become a source of expertise and clinical support for many similar rare diseases. They give clinical recommendations to the family to improve day to day quality of life and also become a medical resource for the local treating care team in the family’s home town.

We are asking that each study center be equipped to be a Center of Excellence for MLD where they can, and do, provide clinical expertise with each visit in addition to gathering the specific NHS data. This approach, as has been demonstrated by the NDRD, is a model that works for research and the families.

We are working to develop a Standard of Care for MLD to further support these clinical Center of Excellence goals and the local treating physicians when they go back home.

To our knowledge, no patients have been recruited for this specific Natural History Study. We hope to impact the collaborative and clinical nature of how the study proceeds before any patients are enrolled, and frankly do not think these requests will impact the core study design in any significant ways. As we all know, once patients are enrolled and data gathering momentum is established, change becomes more difficult.

We have excellent contact and influence with the MLD families worldwide. We are using this position and those relationships to try to affect a fundamental change in how Natural History Studies are implemented for MLD and for all rare diseases.

It is very bold to take this sort of position publicly – but it’s our moral responsibility to stand up for the patients. We firmly believe this “patient-first” while “optimizing research” stance is optimal for patients and researchers.

If your organization supports this philosophy for OPEN Natural History Studies please comment here and then email us to let us know. Advocacy groups can be the catalyst for these changes.

A very interesting question came up today on the MLD Family Discussion List™ (a private list we run for MLD primary caregivers). I thought it might inspire some thinking so I am sharing my answer here as well:

I have a question and I don’t know if anyone has an answer but I am wondering if anyone knows what truly stops this disease? Is it a normal enzyme level? Will the kids stop declining if the enzyme level stays normal? Are there other things that contribute to the stabilization of MLD??

Your first guess is actually correct – we really don’t know. It will take lots of years of careful study looking at extended clinical trial/Phase III data, combined with more basic science bench work, natural history, and lots of patient & clinic reported progression/outcome data to really understand this disease. And on top of a basic understanding we have hundreds of mutations to study. We’re not planning on shutting down the MLD Foundation anytime soon!

From a practical perspective, the generally accepted consensus is that if the enzyme level in the blood is high enough (remember that “normal” levels vary all over the map and carriers with low blood enzyme levels appear to be metabolically “normal” people) then MLD’s progression will be dramatically slowed or halted. There is truth in this first order basic assumption – but it’s just the start of our understanding.

However (and not to scare you), there are three things to consider as we peel the MLD onion one layer (and there will be more subtleties as we further peel the MLD onion again in the future):

1) The first is that enzyme in the blood is of no value – it needs to be in the nerve cells that need it. Today’s therapies are primarily focused at crossing the CNS (central nervous system) into the brain. We measure enzyme levels in the blood and the CNS because it’s possible – brain biopsies on living people are not good! The state of our ability to get enzyme’s large molecules reliably across the blood brain barrier (BBB) is in its infancy and the results are inconsistent at best. The Milano gene therapy acknowledges this challenge by trying to make sure that whatever gets across the BBB produces 5-10x more enzyme than is typical hoping that the overproducing cells will share enzyme with their neighbors. Think of a gas tank in a car – a full tank shows “F” on the dial, but the engine won’t run if the fuel filter (BBB) is blocking the gas from getting to the engine (the brain).

2) The second thing to consider is once enzyme gets past the BBB will it get to all of the cells that need it? Are some/many of those cells already compromised or unreceptive, does the enzyme (actually it’s a protein) get distributed to all regions of the brain, are the cells fixed so they keep on producing the enzyme or are they waiting for anther infusion like Enzyme Replacement Therapy (ERT) is designed to provide? To continue the car analogy – the car may run if only 3 cylinders (brain regions) get fuel (enzyme) but you really need fuel to get to all of the cylinders (regions of the brain) to have the optimal/desired performance.

3) As mentioned, today’s therapies are primarily targeted at the brain/CNS, but our nervous system has a second component, the Peripheral Nervous System (PNS) that needs to be “fixed” as well. The PNS makes sure the messages from the brain/CNS get to the muscles and systems elsewhere in the body. We have historically seen a lot of transplants where the brain progression is slowed (stopped?) but the motor skills continue to decline (witness the many post-transplant children in wheelchairs). The PNS is slightly different in its makeup than the CNS. It also has a barrier, sometimes called the Blood Nerve Barrier (BNB), which is different from the BBB. The common response when we ask why current research is focused on the CNS and not the PNS is that it makes sense to prioritize the CNS. The challenge is that, to our knowledge, very little work has been done on the PNS barrier aspects of MLD. The car analogy is when the engine is running but the car is in neutral – lots of power under the hood but it is not getting to the wheels (limbs & organs) so the car is not going anywhere.

Also remember that some of these therapies require time to take hold. The transplants need to engraft and the “good” cells take over/replace the bad cells before they can be effective. With ERT the thinking is they need to maintain somewhat consistent levels in the CNS which drives dosages and frequency of infusion. Different issues, progressions and concerns will be at different priorities during the various early and long-term phases of each therapy.

And there are other therapies being developed as well … what if we reduced the amount of sulfatides produced so the little bit of enzyme that many MLD patients have doesn’t have to go as far? This is called substrate reduction therapy (SRT) and hopefully will require a small molecule which, like alcohol, can more easily cross the BBB. In the car analogy we still only get a little bit of gas through the clogged fuel filter – but what if the car was lighter and didn’t require as big an engine – their might be enough fuel getting by to be able to get from point A to point B?

We don’t have to completely understand all of this to make progress and see results in therapies. As I mentioned above, the studies will go on for many more years and hopefully, today’s therapies will be good, tomorrows will be better, and in 5 or 10 years they will be even better as we better understand MLD, the body systems and the therapies of today and the future. But for tomorrows therapies to be optimal, we do have to take the time to learn from every patient, every success, every valiant effort, every failure, and to explore every creative idea – many of which will lead us to increased knowledge even thought they are a practical dead-end.

At our upcoming Board meeting we are going to talk about investing in an independent formal MLD Registry to start to capture this scientific and medical history data in a more accessible scientifically managed database – we want the data to be there for future researchers to study when they have a creative idea. And by investing, I don’t just mean a few dollars, I mean that all of us, all of the MLD patients and their families, will be asked to contribute data as we begin to crowdsource MLD research in ways bigger than just one isolated project after another.

Until this morning, I didn’t even know what paroxysmal nocturnal haemoglobinuria (Marchiafava-Micheli syndrome or PNH) was – all I need to know was they are fellow brothers and sisters with rare disease. We must come to their support.

Enough already! Well over 95% of the rare diseases are struggling to understand their disease and develop therapies … yet here we have a disease with a therapy that some bean counting bureaucrat says $$ x number of patients = too much. What they conveniently ignore in their public stance is that Alexion, like all rare disease drug companies, will work with countries that need help to offset the list price because they care about the patient. PHARMAC (New Zealand’s purchasing agency) you should care too!

We must not allow any more piecemeal incursions on the progress we are making towards therapies for all rare diseases. If your disease is lucky enough to have a therapy in the future – the PNH struggle could be yours. We must education and inform now!